High concentration medicant solutions for treating neurological disorders

ABSTRACT

Highly concentrated solutions are disclosed along with methods of inhibiting and/or ameliorating functional neurological disorders of the brain. The method may include administering directly to a brain of a subject a medicament multiple times over a time period of at least two days. The medicament may include a half-life of less than 2 hour in the cerebrospinal fluid. The method may include inhibiting and/or ameliorating a functional neurological disorder of the brain using the medicant.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.62/575,770, filed Oct. 23, 2017, which application is incorporatedherein by reference.

FIELD OF THE INVENTION

The present disclosure generally relates to direct brain administrationof a medicant and includes solutions of a highly concentrateddrug/medicant as well as methods of administering medicants to subjectsto treat functional neurological disorders.

BACKGROUND OF THE INVENTION

The delivery of medications directly to specific parts of the body hasseveral advantages over systemic administration. Lower doses ofmedication can be used with site specific administration and systemictoxicities of drug therapies can be mitigated. Furthermore, deliveryport implantable devices are used regularly in the delivery ofchemotherapy and medications to allow direct administration of certainmedications best administered through direct access to the venoussystem, central nervous system and peritoneal cavity.

In some organs of the body, direct administration of certain drugs maybe required to achieve therapeutic doses of medication without inducingserious toxicity. For example, the blood-brain barrier (BBB) protectsthe brain from potentially toxic substances, but also restricts thepassage of most drug molecules. Because of the BBB, directadministration of drugs may be required to achieve therapeuticconcentrations for the treatment of cancer, neurodegenerative diseasessuch as Alzheimer's (AD) and Parkinson's Disease (PD), and otherconditions.

Alternatively, devices for local, repeatable, and chronic drug deliverycan be used. These devices contain catheters that distribute drug tospecific tissues and may or may not contain a reservoir for storingdrug. These devices include implantable drug pump systems, for example,Ommaya Rickham reservoirs and Port-A-Cath® devices. These devicesdeliver either a bolus or slow infusion of drugs to specific regions ofthe body. The types of drugs that can be used range from painmedications (e.g., morphine) to chemotherapeutics (e.g., methotrexate,cytarabine).

Cerebrospinal fluid (CSF) is a clear, colorless, body fluid found in thebrain and spinal cord. CSF is produced in the choroid plexuses of theventricles of the brain and absorbed in the arachnoid granulations.There is about 125 mL of CSF at any one time, and about 500 mL isgenerated every day. CSF acts, in part, as a cushion for the brain,providing basic mechanical and immunological protection to the braininside the skull. The CSF also serves a vital function in cerebralautoregulation of cerebral blood flow. Chronic administration of smallmolecule medications to the brain CSF is unexplored especiallymedications with short half-lives. The only two molecules that have everbeen looked at chronically are morphine and baclofen which have barelybeen explored but have been used because they already have been used inCSF administration in the spine. Baclofen's half-life is on the order offive hours and morphine's half-life is on the order of two hours.

Acute administration has been looked at primarily in the form of shortterm boluses and primarily for treatment of leptomeningeal disease. Infact, it has been decided that chronic administration of drugs into theCSF will not work for brain disease other than for leptomeningealdisease which is not within the brain itself

CSF flow is typically thought to go from the brain to one lateralventricle, to the third ventricle and fourth and out over and under thebrain convexities before being reabsorbed. In addition, animals havevastly different size and scale to their brains and they unexploredrelative to other bodily organs and systems. The animals used in mosttesting of CSF flow is rats who have a 111000 the size of the humanbrain and even primates have a brain which is at best 1/10th the size ofthe human brain for large experimental primates. Furthermore, clinicalresults are expected to be different in human subjects than in animals.As a result of these and other factors allometric scaling is expected tobe vastly off Allometric equations take the general form Y=aM h, where Yis some biological variable, M is a measure of body size, and b is somescaling exponent. In allometry, equations are often presented inlogarithmic form so that a diverse range of body sizes can be plotted ona single graph.

It would be desirable, therefore, to determine a method, system,composition, and/or protocol resulting in the successful chronicadministration of medications with short half-lives directly to thebrain.

SUMMARY OF THE INVENTION

Highly concentrated solutions are disclosed along with methods ofinhibiting and/or ameliorating functional neurological disorders of thebrain. The method may include administering directly to a brain of asubject a medicament multiple times over a time period of 2, 3, 4, 6, 6,7 days or more. The medicament may include a half-life of less than oneday, 16 hours, 8 hours, 4 hours or 2 hours in the cerebrospinal fluid.The method may include inhibiting and/or ameliorating a functionalneurological disorder of the brain using the medicament.

In some embodiments, the medicament may include valproic acid orpharmaceutically active derivatives thereof. In some embodiments, themedicament comprises a half-life of less than about 30 minutes in thecerebrospinal fluid. In some embodiments, during treatment themedicament is continuously delivered in an amount so as to maintain aconcentration in the cerebrospinal fluid of between 1 to 500micrograms/ml, or 5 to 200 micrograms/ml or 50 micrograms/ml ±20%, ±10%,±5% over a period of 1, 2, 3, 4, 5, 6, 7 or more days. In someembodiments, there is a substantially linear relationship between aconcentration of the medicament in the cerebrospinal fluid and a dailydosage of the medicament.

The functional neurological disorder may include, Epilepsy, StatusEpilepticus, Bipolar, Bipolar Spectrum Disorder, Post Traumatic StressDisorder or Other Epilepsy, Bipolar Spectrum and Anxiety RelatedDisorder.

In some embodiments, administering directly via a catheter to thecerebrospinal fluid of a subject's brain may include substantiallycontinuous administration of the medicament during treatment via acatheter to the cerebrospinal fluid. In some embodiments, dosage isbased upon a desired daily dosage of the medicament and the medicament'shalf-life in the cerebrospinal fluid. Administering directly to asubject's brain may include continuously administering a dosage of themedicament such that a concentration of about 50 micrograms/ml ±20%,±10%, ±5% over a period of 1, 2, 3, 4, 5, 6, 7 or more days ismaintained in the cerebrospinal fluid during a treatment periodeffective to provide a meaningful therapeutic benefit to the patient.

In some embodiments, administering directly via a catheter to thecerebrospinal fluid to a subject's brain may include administeringmultiple bolus pulses of the medicament during treatment. A dosage maybe based upon a target treatment dosage of the medicament and themedicament's half-life in the cerebrospinal fluid such that the targettreatment dosage during a treatment period is multiplied by a number ofhalf-lives lost occurring during the gaps in the treatment period toachieve a meaningful target therapeutic levels. Administering directlyto a subject's brain comprises administering multiple bolus pulses adosage of the medicament such that an average concentration of 1 to 500micrograms/ml, or 5 to 200 micrograms/ml or 50 micrograms/ml ±20%, ±10%,±5%, is maintained in the cerebrospinal fluid during a treatment periodof time sufficient to provide a meaningful benefit to the patient.

In some embodiments, the medicament may include valproic acid orpharmaceutically active derivatives thereof. The dosage may bedetermined using a relationship defined by valproic acid concentrationin micrograms per milliliter is approximately equivalent to dose invalproic acid dose mg/day. So for example a concentration of 50milligrams per day is equal to approximately 50 micrograms per ml.

In some embodiments, the method may include monitoring administration ofthe medicament by monitoring a subject's perception of the subject'sbody temperature.

In some embodiments, the medication may be only administered to onelateral brain ventricle on one side of the brain and not bilaterallyadministered to both ventricles.

In some embodiments the medication maybe administered to the thirdventricle, cisterna magna, or basilar cisterns.

In some embodiments, the concentration may be determined by samplingcerebrospinal fluid from the lateral ventricle or third ventricle orcisterna Magna or basilar cisterns and determining a concentration ofthe medicament and/or a derivative thereof to adjust up or down theinfusion amount (by changing the daily flow rate and/or theconcentration of the infused medication) to achieve an improvement inthe clinical symptoms.

In some embodiments, a chemical compound may function to inhibit and/orameliorate functional neurological disorders of the brain. The chemicalcompound may include a medicament administering directly to a brain of asubject. The medicament may be administered as part of a pharmaceuticalcomposition. The medicament may include a half-life of less than 0.5, 1,2, 4, 8 or 16 hours in the cerebrospinal fluid. The medicament mayinhibit and/or ameliorate and/or modify a functional neurologicaldisorder of the brain. The medicament may include a solubility of 10,25, 50, 100 or 200 mg/ml.

In some embodiments, the medicament comprises valproic acid orpharmaceutically active derivatives thereof. The dosage may bedetermined using a relationship defined by log (valproic acidconcentration) is approximately equivalent to log (valproic acid dosemg/day) minus a fixed number between about 3 to about 30.

In some embodiments of the invention, additional excipient materials areincluded within the formulation with the drug which may be valproicacid. The excipients can be citric acid which can be a form of a citrateand be present in an amount in a range of 0.1 to 4% by weight or 0.2 to2% by weight or 0.4%±10%. The formulation may also include an acetatebuffer in a concentration of one to 25 millimolar or 10 millimolar, asodium phosphate buffer in an amount of 10 to 50 millimolar or about 20millimolar, and saline in an amount of 10 to 50 millimolar or about to20 millimolar.

These and other objects, advantages, and features of the invention willbecome apparent to those persons skilled in the art upon reading thedetails of the formulations, uses thereof and methods of treatment asmore fully described below.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is best understood from the following detailed descriptionwhen read in conjunction with the accompanying drawings. It isemphasized that, according to common practice, the various features ofthe drawings are not to-scale. On the contrary, the dimensions of thevarious features are arbitrarily expanded or reduced for clarity.Included in the drawings are the following figures:

FIG. 1 depicts a graph of a concentration of valproate in blood serum ofhuman subjects over time after the valproate has stop being administeredfor a week.

FIG. 2 depicts a graph of a concentration of valproate in cerebrospinalfluid of human subjects over time after the valproate has stop beingadministered for a week.

FIG. 3 depicts a graph of a concentration of valproate in cerebrospinalfluid and blood serum of a human subject over time after the valproatehas stop being administered for a week.

FIG. 4 depicts a graph of targeted concentration of valproate incerebrospinal fluid verses an actual concentration of valproate incerebrospinal fluid.

FIG. 5 depicts a graph of a relationship between valproic acidconcentration cerebrospinal fluid and a dosage of valproic acid.

FIG. 6 depicts a graph of how long it takes to reach a targetedconcentration of valproate using different dosage rates.

FIG. 7 depicts a graph of pH titrations of different sodium valproatesolutions (5 mL) by progressively adding 0.1 mL of 25 mM HCl.

While the invention is susceptible to various modifications andalternative forms, specific embodiments thereof are shown by way ofexample in the drawings and may herein be described in detail. Thedrawings may not be to scale. It should be understood, however, that thedrawings and detailed description thereto are not intended to limit theinvention to the particular form disclosed, but on the contrary, theintention is to cover all modifications, equivalents and alternativesfalling within the spirit and scope of the present invention as definedby the appended claims.

The headings used herein are for organizational purposes only and arenot meant to be used to limit the scope of the description. As usedthroughout this application, the word “may” is used in a permissivesense (i.e., meaning having the potential to), rather than the mandatorysense (i.e., meaning must). The words “include,” “including,” and“includes” indicate open ended relationships and therefore meanincluding, but not limited to. Similarly, the words “have,” “having,”and “has” also indicated open-ended relationships, and thus mean having,but not limited to. The terms “first,” “second,” “third,” and so forthas used herein are used as labels for nouns that they precede, and donot imply any type of ordering (e.g., spatial, temporal, logical, etc.)unless such an ordering is otherwise explicitly indicated. For example,a “third die” electrically connected to the module substrate” does notpreclude scenarios in which a “fourth die electrically connected to themodule substrate” is connected prior to the third die, unless otherwisespecified. Similarly, a “second” feature does not require that a “first”feature be implemented prior to the “second” feature, unless otherwisespecified.

Various components may be described as “configured to” perform a task ortasks. In such contexts, “configured to” is a broad recitation generallymeaning “having structure that” performs the task or tasks duringoperation. As such, the component can be configured to perform the taskeven when the component is not currently performing that task (e.g., aset of electrical conductors may be configured to electrically connect amodule to another module, even when the two modules are not connected).In some contexts, “configured to” may be a broad recitation of structuregenerally meaning “having circuitry that” performs the task or tasksduring operation. As such, the component can be configured to performthe task even when the component is not currently on. In general, thecircuitry that forms the structure corresponding to “configured to” mayinclude hardware circuits.

Various components may be described as performing a task or tasks, forconvenience in the description. Such descriptions should be interpretedas including the phrase “configured to.” Reciting a component that isconfigured to perform one or more tasks is expressly intended not toinvoke 35 U.S.C. § 112 paragraph (f), interpretation for that component.

The scope of the present disclosure includes any feature or combinationof features disclosed herein (either explicitly or implicitly), or anygeneralization thereof, whether or not it mitigates any or all of theproblems addressed herein. Accordingly, new claims may be formulatedduring prosecution of this application (or an application claimingpriority thereto) to any such combination of features. In particular,with reference to the appended claims, features from dependent claimsmay be combined with those of the independent claims and features fromrespective independent claims may be combined in any appropriate mannerand not merely in the specific combinations enumerated in the appendedclaims.

It is to be understood the present invention is not limited toparticular devices or biological systems, which may, of course, vary. Itis also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only and is not intended tolimiting. As used in this specification and the appended claims, thesingular forms “a”, “an”, and “the” include singular and pluralreferents unless the content clearly dictates otherwise. Thus, forexample, reference to “a linker” includes one or more linkers.

It is to be understood that terms such as “about” or “substantially” orother similar terms when used in combination with numerical descriptorsare interpreted as meaning +/−10% unless defined alternatively hereinand/or as defined by the state of the art.

DETAILED DESCRIPTION OF THE INVENTION

Before the present formulations, uses thereof and methods of treatmentare described, it is to be understood that this invention is not limitedto particular embodiments described, as such may, of course, vary. It isalso to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting, since the scope of the present invention will be limitedonly by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, some potential andpreferred methods and materials are now described. All publicationsmentioned herein are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. It is understood that the present disclosuresupersedes any disclosure of an incorporated publication to the extentthere is a contradiction.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “anadministration” includes a plurality of such administrations or dosesand reference to “the bolus” includes reference to one or more bolusdoses and equivalents thereof known to those skilled in the art, and soforth.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art.

The terms “administration,” “administering,” or the like, as used hereinwhen used in the context of providing a pharmaceutical, cosmeceutical ornutraceutical composition to a subject generally refers to providing tothe subject one or more pharmaceutical, “over-the-counter” (OTC) ornutraceutical compositions in combination with an appropriate deliveryvehicle by any means such that the administered compound achieves one ormore of the intended biological effects for which the compound wasadministered. By way of non-limiting example, a composition may beadministered parenteral, subcutaneous, intravenous, intracoronary,rectal, intramuscular, intra-peritoneal, transdermal, or buccal routesof delivery. Alternatively, or concurrently, administration may be bythe oral route. The dosage of pharmacologically active compound that isadministered will be dependent upon multiple factors, such as the age,health, weight, and/or disease state of the recipient, concurrenttreatments, if any, the frequency of treatment, and/or the nature andmagnitude of the biological effect that is desired.

The term “bolus” as used herein generally refers to a single dose of adrug or other medicinal preparation given all at once.

The term “catheter” as used herein generally refers to medical devicesthat can be inserted in the body to treat diseases or perform a surgicalprocedure.

The term “connected” as used herein generally refers to pieces which maybe joined or linked together.

The term “coupled” as used herein generally refers to pieces which maybe used operatively with each other, or joined or linked together, withor without one or more intervening members.

The term “directly” as used herein generally refers to one structure inphysical contact with another structure, or, when used in reference to aprocedure, means that one process effects another process or structurewithout the involvement of an intermediate step or component.

The terms “effective concentration” or “effective amount” as used hereingenerally refers to a sufficient amount of the pharmaceutically activeagent that is added to decrease, prevent or inhibit the growth of avirus and/or cancerous growth. The amount will vary for each compoundand upon known factors related to the item or use to which thepharmaceutically active agent is applied.

The term “functional neurological disorder” as used herein generallyrefers to a condition in which a brain of a subject is structurallynormal (or at least has no significant structural abnormalities), butfunctions incorrectly. The disorder may lead to the subject experiencingneurological symptoms such as weakness, movement disorders, sensorysymptoms, seizures, and blackouts.

The terms “in need of treatment” or “in need thereof” when used in thecontext of a subject being administered a pharmacologically activecomposition, generally refers to a judgment made by an appropriatehealthcare provider that an individual or animal requires or willbenefit from a specified treatment or medical intervention. Suchjudgments may be made based on a variety of factors that are in therealm of expertise of healthcare providers but include knowledge thatthe individual or animal is ill, will be ill, or is at risk of becomingill, as the result of a condition that may be ameliorated or treatedwith the specified medical intervention.

The term “malady” as used herein generally refers to any disorder ordisease of the body or any undesirable or disordered conditionincluding, but not limited to, illness, sickness, affliction, complaint,ailment, indisposition, virus, disease, fungus, infection, disease, etc.

The term “medicant” as used herein generally refers a medicinalsubstance used or to prevent, cure, or relieve disease.

Terms such as “pharmaceutical composition,” “pharmaceuticalformulation,” “pharmaceutical preparation,” or the like, are used hereinto generally refer to formulations that are adapted to deliver aprescribed dosage of one or more pharmacologically active compounds to acell, a group of cells, an organ or tissue, an animal or a human.Methods of incorporating pharmacologically active compounds intopharmaceutical preparations are widely known in the art. Thedetermination of an appropriate prescribed dosage of a pharmacologicallyactive compound to include in a pharmaceutical composition in order toachieve a desired biological outcome is within the skill level of anordinary practitioner of the art. A pharmaceutical composition may beprovided as sustained-release or timed-release formulations. Suchformulations may release a bolus of a compound from the formulation at adesired time or may ensure a relatively constant amount of the compoundpresent in the dosage is released over a given period of time. Termssuch as “sustained release,” “controlled release,” or “timed release”and the like are widely used in the pharmaceutical arts and are readilyunderstood by a practitioner of ordinary skill in the art.Pharmaceutical preparations may be prepared as solids, semi-solids,gels, hydrogels, liquids, solutions, suspensions, emulsions, aerosols,powders, or combinations thereof. Included in a pharmaceuticalpreparation may be one or more carriers, preservatives, flavorings,excipients, coatings, stabilizers, binders, solvents and/or auxiliariesthat are, typically, pharmacologically inert. It will be readilyappreciated by an ordinary practitioner of the art that, included withinthe meaning of the term are pharmaceutically acceptable salts ofcompounds. It will further be appreciated by an ordinary practitioner ofthe art that the term also encompasses those pharmaceutical compositionsthat contain an admixture of two or more pharmacologically activecompounds, such compounds being administered, for example, as acombination therapy.

The term “pharmacologically inert,” as used herein, generally refers toa compound, additive, binder, vehicle, and the like, that issubstantially free of any pharmacologic or “drug-like” activity.

The terms “reducing,” “inhibiting” and “ameliorating,” as used herein,when used in the context of modulating a pathological or disease state,generally refers to the prevention and/or reduction of at least aportion of the negative consequences of the disease state. When used inthe context of an adverse side effect associated with the administrationof a drug to a subject, the term(s) generally refer to a net reductionin the severity or seriousness of said adverse side effects. The term“subject” as used herein generally refers to a mammal, and in particularto a human.

The phrase “therapeutically effective amount” generally refers to anamount of a drug or pharmaceutical composition that will elicit at leastone desired biological or physiological response of a cell, a tissue, asystem, animal or human that is being sought by a researcher,veterinarian, physician or other caregiver.

ADMINISTRATION EMBODIMENTS

Herein described is a very short half-life medicant useful for treatinga disease of the brain. Typically, medicants used for treating diseasesof the rain, especially functional neurological disorder, haverelatively long half-lives on the order of two hours or longer, andexcept for morphine, typically much longer than two hours. The reasonsmedicants with long half-lives are used is obvious and due at least inpart to the fact that it is difficult to achieve therapeutic levels of amedicant in a subject if the medicant is decomposing too quickly. Thiscan be especially problematic due to the manner in which medicants aretypically administered in a general matter (e.g., orally, intravenously,etc.) to a subject as opposed to a specific regional administration(e.g., topically to a regional skin condition. When medicants areadministered generally (e.g., orally in order to treat a specific regionof the body not orally associated) they can take time to diffuse throughthe subject's body and accumulate in appreciable levels in the specificregion requiring medicants with a substantial half-life.

In some embodiments, a chemical composition and/or method may includeinhibiting and/or ameliorating functional neurological disorders of thebrain. In some embodiments, functional neurological disorders of thebrain may include epilepsy. In other embodiments, functionalneurological disorders of the brain may include Bipolar and BipolarSpectrum Disorder. In some embodiments, the functional neurologicaldisorder may include Post Traumatic Stress Disorder or Other AnxietyRelated Disorder.

The term “functional neurological disorder” as used herein generallyrefers to a condition in which a brain of a subject is structurallynormal (or at least has no significant structural abnormalities), butfunctions incorrectly. The disorder may lead to the subject experiencingneurological symptoms such as weakness, movement disorders, sensorysymptoms, seizures, and blackouts.

The method may include administering one or more medicants directly to abrain of a subject. A medicant may be administered chronically.Generally chronic administration may include any medicant paradigm wherethe medicant is given during more than one experimental session.However, it should be noted that each experimental session may involvemultiple doses or drug doses and behavioral paradigms. Typically, aparadigm may be considered chronic if it was repeated over many days fora subject Chronic administration may include multiple times over a timeperiod of at least two days. In contrast acute administration of amedicant may be generally defined as a drug administration paradigmwhere a drug is given during one experimental session (once during theexperiment, or multiple times) within a 24-hour period.

Chronic administration may include continuous administration of amedicant during a treatment period. In some embodiments, administeringdirectly to a subject's brain may include substantially continuousadministration of the medicant during treatment.

In some embodiments, administering directly to a subject's brain mayinclude administering multiple bolus pulses of the medicant duringtreatment. Bolus pulses in general may be described as theadministration of a medicant in a single, large dose which might berepeated after an interval of days. Thought to have the advantage ofhigh tissue levels and fewer of the undesirableside-effects associatedwith more frequent dosing. In some embodiments, herein bolus pulses maybe considered as the administration of a medicant multiple times whereinthe time between administration is greater than a half-life of themedicant. A dosage may be based upon a target treatment dosage of themedicant and the medicant's half-life in the cerebrospinal fluid suchthat the target treatment dosage during a treatment period is multipliedby a number of half-lives lost occurring during the gaps in thetreatment period to achieve a meaningful target therapeutic levels.

In some embodiments, a dosage is based upon a desired daily dosage ofthe medicant and the medicant's half-life in the cerebrospinal fluid.Cerebrospinal fluid medicant concentration levels are a better predictorof concentration levels of the medicant in the brain relative to, forexample, blood serum levels which are not a good predictor andunreliable. FIG. 1 depicts a graph of a concentration of valproate inblood serum of human subjects over time after the valproate has stopbeing administered for a week. The subjects have been administereddifferent dosage levels of valproate using different concentrations ofvalproate in solution. As can be seen in FIG. 1 valproate concentrationswere quite erratic and unpredictable relative to the valproate dosage.FIG. 2 depicts a graph of a concentration of valproate in cerebrospinalfluid of human subject over time after the valproate has stop beingadministered for a week. The subjects have been administered differentdosage levels of valproate using different concentrations of valproatein solution. As can be seen the concentration of valproate drops quicklyas would be expected due to the short half-life of valproate. FIG. 3depicts a graph of a concentration of valproate in cerebrospinal fluidand blood serum of a human subject over time after the valproate hasstop being administered for a week. The subject has been administered 60mg/day total of valproate using a pump which provides direct regionaladministration of valproate to the subject's brain using a 100 mg/mLsolution. FIG. 3 further demonstrates that testing cerebrospinal fluidis a far better predictor of medicant concentrations than is serum.

In some embodiments, a substantially linear relationship between aconcentration of the medicant in the cerebrospinal fluid and a dailydosage of the medicant. In some embodiments, the concentration of themedicant and/or a derivative thereof may be determined by samplingcerebrospinal fluid from the lateral ventricle to adjust up or down theinfusion amount (by changing the daily flow rate and/or theconcentration of the infused medication) to achieve an improvement inthe clinical symptoms. This linear relationship allows for a greatlyincreased chance of a caregiver accurately hitting a desired valproatedosage target FIG. 4 depicts a graph of targeted concentration ofvalproate in cerebrospinal fluid verses an actual concentration ofvalproate in cerebrospinal fluid.

In some embodiments, the dosage may be determined using a relationshipdefined by log (valproic acid concentration) is approximately equivalentto log (valproic acid dose mg/day).

The dosage may be determined using a relationship defined by log(valproic acid concentration) is equivalent to log (valproic acid dosemg/day) minus a fixed number between about 0 to about. In someembodiments, the dosage may be determined using a relationship definedby log (valproic acid concentration) is equivalent to log (valproic aciddose mg/day) minus a fixed number between about 3 to about 30.

In some embodiments, the medicant may include valproic acid orpharmaceutically active derivatives thereof. The dosage may bedetermined using a relationship defined by log (valproic acidconcentration) is approximately equivalent to log (valproic acid dosemg/day). The dosage may be determined using a relationship defined bylog (valproic acid concentration) 10 is equivalent to log (valproic aciddose mg/day) minus 3.

One must have the cerebrospinal fluid concentration levels high enoughso that the cerebrospinal fluid drives the medicant into the brainduring the natural flow of cerebrospinal fluid through the brain. FIG. 5depicts a graph of a relationship between valproic acid concentration incerebrospinal fluid and a dosage of valproic acid. The graph depicts thedosage range wherein no efficacy was observed as well as the dosagewherein different toxicities for various organs are known. Administeringdirectly to a subject's brain may include administering a dosage of themedicant such that an average concentration of at least 10 micrograms/mLis maintained in the cerebrospinal fluid during a treatment period. Anaverage concentration may be used when multiple bolus pulses are used toadminister the medicant. If continuous or substantially continuousadministration is used to deliver a medicant then a concentration of atleast 10 micrograms/mL is maintained in the cerebrospinal fluid during atreatment period. In some embodiments, during treatment the medicant hasa concentration in the cerebrospinal fluid of between about 10micrograms/mL to about 150 micrograms/mL. FIG. 6 depicts a graph of howlong it takes to reach a targeted concentration of valproate usingdifferent dosage rates. It is nonobvious to scale dosage from animals tohumans. When results from animal trials have been used to scale humandosages the resulting dosages can be off by as much as 400%. Therefore,human data is very important.

In some embodiments, the medicant may include a half-life of less than 2hour in the cerebrospinal fluid. In some preferred embodiments, themedicant may include a half-life of less than 1 hour in thecerebrospinal fluid. The method may include inhibiting and/orameliorating a functional neurological disorder of the brain using themedicant. In some embodiments, the medicant may include valproic acid orpharmaceutically active derivatives thereof. In some embodiments, themedicant may include a half-life of less than about 30 minutes in thecerebrospinal fluid (e.g., valproic acid or pharmaceutically activederivatives thereof).

Cerebrospinal fluid flow is typically thought to go from the brain toone lateral ventricle, to the third ventricle and fourth and out overand under the brain convexities before being reabsorbed. It has beenfound, surprisingly and unexpectedly, that the ventricles appear to mix.In some embodiments, the medicant may be only administered to onelateral brain ventricle on one side of the brain while stilladministering medicant to both ventricles. Due to this discovery themedicant may not require administration bilaterally to both ventriclesin order to provide medicant to both ventricles.

In some embodiments, the method may include monitoring administration ofthe medicant by monitoring a subject's perception of the subject's bodytemperature sensation and/or feeling of being nauseous. It has beenfound in all of a group of subjects as they have gotten to therapeuticlevels of administered medicants that they have felt cold. This is anunexpected and unprecedented result and one assumes that highermedication doses have changed the hypothalamus. It was initially thoughtthat there should be concern around the dosage but subjects rapidlyacclimated to these symptoms and found a benefit. Interestingly, ittells the clinician that it is a sign of clinical improvements furtherdiscussed in the examples.

High Concentration Embodiments

Sodium valproate is used clinically at concentrations of 100 mg/mL orless. Like any weak acid, the valproate molecule will be charged aboveits pKa value (4.8), and thus more readily soluble at high pH. Despiteits charged character at high pH, solubility limits in water arecommonly reported as 50-100 mg/mL. Indeed, this is quite concentratedfor any solute, with 100 mg/mL equivalent to a 10% solution. Given thereported solubility limit, it was unexpected when experimentsdemonstrated that sodium valproate fully dissolves and forms clear,homogeneous aqueous solutions up to at least 500 mg/mL. In someembodiments, sodium valproate may have a concentration of greater than200 mg/mL, greater than 300 mg/mL, or greater than 400 mg/mL.

Given a pKa of 4.8, it would be expected based upon acceptedgeneralizations that a concentrated solution of sodium valproate wouldhave a pH within about 1 pH unit of the pKa. Therefore, a solutionbuffered by sodium valproate should resist pH changes between pH3.8-5.8, with minimal buffering capacity (β) above pH 5.8. However, asolution of 150 mg/mL sodium valproate in water yields a pH ofapproximately 8.3. More concentrated solutions (>350 mg/mL) possess pHvalues above 9. This unexpected finding indicates that sodium valproateis much more soluble than is commonly reported.

FIG. 7 depicts a graph pH titrations of different sodium valproatesolutions (5 mL) by progressively adding 0.1 mL of 25 mM HCl. A typicalbuffer concentration is 10 mM, which is equivalent to 1.7 mg/mL sodiumvalproate: about 90-fold than embodiments depicted herein. If you lookat the line depicting the titration of 10 mM sodium valproate (opensquares in FIG. 7), one can see that the pH changes from 6.6 to 4.36 as1 mL of acid is added in 0.1 mL increments. The pH of this solution hitsthe pKa after 0.6 mL of 25 mM HCl is added; this is the point of maximumbuffering capacity. Although it is difficult to clearly discern by eye,the pH change (4.81 to 4.74) is minimized as an additional 0.1 mL acidis added (i.e., going from 0.6 mL to 0.7 mL as compared to any otheraddition of 0.1 mL acid). This is the experimental illustration of themaximum buffer capacity that can be calculated from the Van Slyke bufferequation:

$\beta = {2.3\; C\frac{K_{a}\left\lbrack {H_{3}O^{+}} \right\rbrack}{\left( {K_{a} + \left\lbrack {H_{3}O^{+}} \right\rbrack} \right)^{2}}}$

When calculated the maximum buffer capacity of 10 mM sodium valproate(i.e., at pH=pKa=4.8), one gets a value of 5.75×10-3. For comparison,blood has a buffer capacity of 3.9×10-2. One can see from the graphdepicted in FIG. 7 that the change in pH of 150 mg/mL sodium valproateis minimal, indicating that it acts like a buffer well above (>3 pHunits) its pKa. FIG. 7 illustrates that the addition of 0.4% sodiumcitrate has virtually no effect on the buffer capacity of 150 mg/mLsodium valproate. If one looks at the last two points in the titrationcurve of 150 mg/mL sodium valproate, the pH changes from 7.34 to 7.30,indicating a very strong buffering capacity even though this is 2.5 pHunits above the pKa of sodium valproate. According to the Van Slykeequation, the calculated (theoretical) buffer capacity of 150 mg/mLsodium valproate at pH 7.4 is roughly equivalent (β=5.19×10-3) to thatseen in the typical buffer (10 mM) at its maximum buffer capacity(pH=4.8). In short, this demonstrates that 150 mg/mL sodium valproateacts as a buffer at physiological pH (pH=7.4) that is equivalent instrength to the maximum buffer capacity achieved at a “typical” bufferconcentration at pH 4.8, and this is consistent with the pH changes upontitration observed. This is unexpected in the sense that this strongbuffer capacity is observed well outside of the range expected for atypical buffer solution with a pKa of 4.8. The fact that this isobserved is consistent with the equation described above, so it could beargued that this behavior is predicted from basic theory. However,because this high concentration of buffer species is so different fromnormal buffer solutions it is unexpected, i.e., formulation scientiststypically use the “rule of thumb” of ±1 pH unit from the pKa.

Concerns about potential precipitation during administration due toeither reduced pH or contaminating metal ions prompted us to exploresodium citrate as both a buffering component and a chelator of metalions. Because citrate has a pKa of 6.4, incorporation of citrate intosodium valproate solutions should fortify buffering in the physiologicalpH range. Citrate may chelate trace metal ions that may becomesolubilized/released within the pump. Considering the unexpectedlystrong buffering by sodium valproate (described above), additionalbuffering capacity may not be necessary. Indeed, results with solutionsof 150 mg/mL (0.9 M) sodium valproate with or without 0.4% sodiumcitrate (13.6 mM) indicate that this low level of citrate does notprovide any measurable increase in buffering capacity above pH 7, nordoes it significantly change the initial pH of these solutions.Nonetheless, inclusion of sodium citrate as a cation/metal chelator mayprovide an improved formulation. It is worth noting that citrate isnaturally present in cerebral spinal fluid. The natural presence ofcitrate in cerebral spinal fluid indicates that citrate should be safewhen used in a pharmaceutical composition.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Example 1 Bilateral Infusion Data

PERCEPTION OF BODY TEMPERATURE: Subjects 01-01, 01-03 and 01-04 all havereported they are always cold—every week that is one of the things theymention—initially I think Mark attributed it to the surgery, but I knowthat No 1 and No 3 are still claiming they always feel cold. It will beinteresting to see what they are like when the weather warms up. Number1 says she has to always put the heater and extra layers on, andsometimes she is so cold her teeth chatter. No 3 is very underweight sobut when she comes for refills needs lots of warm blankets and is alwayswearing lots of layers. No 4 said he was cold for the short time he wasreceiving the Valproate as well (3 weeks). No 2 hasn't really said shewas cold but as discussed, she has some other issues as discussed but Iwill ask her Friday. I will ask no 5 tomorrow is she feels cold as lastweek as she has had one week “on” the Valproate and she is currentlycompleting her placebo week so hasn't really had the active treatmentfor long. The other thing all the patients say when they reach atherapeutic level they also have a feeling of nauseous which seems topass over time.

In this patent, certain U.S. patents, U.S. patent applications, andother materials (e.g., articles) have been incorporated by reference.The text of such U.S. patents, U.S. patent applications, and othermaterials is, however, only incorporated by reference to the extent thatno conflict exists between such text and the other statements anddrawings set forth herein. In the event of such conflict, then any suchconflicting text in such incorporated by reference U.S. patents, U.S.patent applications, and other materials is specifically notincorporated by reference in this patent.

Further modifications and alternative embodiments of various aspects ofthe invention will be apparent to those skilled in the art in view ofthis description. Accordingly, this description is to be construed asillustrative only and is for the purpose of teaching those skilled inthe art the general manner of carrying out the invention. It is to beunderstood that the forms of the invention shown and described hereinare to be taken as the presently preferred embodiments. Elements andmaterials may be substituted for those illustrated and described herein,parts and processes may be reversed, and certain features of theinvention may be utilized independently, all as would be apparent to oneskilled in the art after having the benefit of this description of theinvention. Changes may be made in the elements described herein withoutdeparting from the spirit and scope of the invention as described in thefollowing claims.

The high pH of these solutions suggests that sodium valproate at highconcentrations is capable of acting as a buffer well above it pKa.Typically, the useful range of a buffer is estimated to be about 1 pHunit above/below its pKa. Thus, sodium valproate would be expected to beuseful as a buffer at pH 3.8-5.8. Accordingly, sodium valproatesolutions should have little capacity to resist changes in pH outside ofthis range. Indeed, it was expected that solutions of sodium valproatecould be easily titrated down to physiological pH (7-7.4), and that thiswould require the addition of a buffer (e.g., phosphate, Tris, citrate)to maintain sodium valproate solutions in the physiological pH range.Unexpectedly, our experiments indicate that these concentrated solutionsof sodium valproate strongly buffer solutions at pH>8, and significantquantities of acid are required to lower the pH into the physiologicalrange. Again, considering the pKa of 4.8, one would expect minimalbuffering of sodium valproate above pH 6, but this is not the case.Accordingly, concentrated solutions of sodium valproate are not onlyreadily prepared by dissolving at room temperature, they bufferthemselves at pH values well above that predicted by their pKa. Thisunexpected property suggests that highly concentrated aqueous solutionsof sodium valproate are homogenous and maintain stable pH; suitable forparenteral administration and prolonged storage within a pump.

Concerns about potential precipitation during administration due toeither reduced pH or contaminating metal ions prompted us to exploresodium citrate as both a buffering component and a chelator of metalions. Because citrate has a pKa of 6.4, incorporation of citrate intosodium alproate solutions should fortify buffering in the physiologicalpH range. Citrate may chelate trace metal ions that may becomesolubilized/released within the pump.

Considering the unexpectedly strong buffering by sodium valproate(described above), additional buffering capacity may not be necessary.Indeed, results with solutions of 150 mg/mL (0.9 M) sodium valproatewith or without 0.4% sodium citrate (13.6 mM) indicate that this lowlevel of citrate does not provide any measurable increase in bufferingcapacity above pH 7, nor does it significantly change the initial pH ofthese solutions. Nonetheless, inclusion of sodium citrate as acation/metal chelator may provide an improved formulation. It is worthnoting that citrate is naturally present in cerebral spinal fluid. Thenatural presence of citrate in cerebral spinal fluid indicates thatcitrate should be safe when used in a pharmaceutical composition.

Example 2 Perception of Body Temperature

Subjects 01-01, 01-03 and 01-04 all have reported they are alwayscold—every week that is one of the things they mention initially I. Markattributed it to the surgery, but I know that No 1 and No 3 are stillclaiming they always feel cold. It will be interesting to see what theyare like when the weather warms up. Number 1 says she has to always putthe heater and extra layers on, and sometimes she is so cold her teethchatter. No 3 is very underweight so but when she comes for refillsneeds lots of warm blankets and is always wearing lots of layers. No 4said he was cold for the short time he was receiving the Valproate aswell (3 weeks). No 2 hasn't really said she was cold but as discussed,she has some other issues as discussed but I will ask her Friday. I willask no 5 tomorrow is she feels cold as last week as she has had one week“on” the Valproate and she is currently completing her placebo week sohasn't really had the active treatment for long. The other thing all thepatients say when they reach a therapeutic level they also have afeeling of nauseous which seems to pass over time.

Example 3

Avoid late interaction or degradation related to Titanium Pump

On the development of highly concentrated formulations of sodiumvalproate:

We initially explored the potential of developing a formulationcontaining emulsified droplets of pure valproic acid (a liquid) toachieve higher concentrations that the reported solubility limit ofsodium valproate (50-100 mg/mL). In the early experiments with theliquid form of valproic acid, it was found that the droplets of valproicacid were dissolving into the water, complicating the development of astable emulsion (an emulsion is only possible if one phase is notsoluble in the other phase). In the course of these experiments, it alsobecame evident that the reported solubility limit of sodium valproatewas grossly inaccurate, and we could dissolve very high concentrationsin water; up to at least 500 mg/mL. Therefore, it was unnecessary to gothrough the work of developing a stable emulsion (in fact, this would bequite difficult considering its high solubility), and that highconcentrations of the drug could be achieved as a solution. Accordingly,we opted to pursue a single phase solution of highly concentrated sodiumvalproate.

On the use of citrate in ICV formulations:

Our initial formulations did not include citrate. When problems with thepump were reported, we assumed that the tubing was clogged, andtherefore that some precipitation/aggregation had occurred. Knowing thatthe formulation was well below the solubility limit of sodium valproate(see above), we then hypothesized about what could be causing aprecipitate to form. It is important to recognize that the potential forprecipitation/aggregation is increased in very concentrated formulationslike those we are developing. Also, it is well-known that metal ions candesorb from any metallic surface, and interact with molecules insolution. Typically, metal ions are desorbed as cationic species thatare likely to interact with anionic molecules (e.g., valproic acid). Inaddition, metal ions can catalyze oxidation reactions (e.g., Fentonchemistry) that degrade the drug molecule into inactive species that maybe more prone to precipitation/aggregation. For this reason, excipientsthat bind metal ions (i.e., chelators) are often used in pharmaceuticalformulations to reduce the potential for physical (precipitation) andchemical (oxidation) degradation. In fact, Depacon (an IV-injectablesolution of sodium valproate) contains EDTA, and we speculated that thismight be added for its ability to chelate metals, thereby stabilizingthe solution. In considering a chelator that would be suitable for ICVadministration, we were concerned that EDTA would chelate calcium whichcould interfere with neuronal activity. In searching for other chelatorsthat might be compatible with the brain, we learned that citrate was anatural component of CSF, and thus would be compatible with this routeof administration.

In addition to metal-induced precipitation, the other possibility thatoccurred to us was a precipitation event due to changes in pH. Wereasoned that a buffering agent that prevented pH changes would also bebeneficial. Since it is advantageous to develop formulations at nearphysiological pH (well above the pKa of sodium valproate; 4.8), it wouldbe desirable to include a buffer species possessing a higher Kasuch thatit would prevent a decrease in pH. In this regard, citrate also servedthat function, and it has three pKa's (3.13, 4.76 and 6.40) that wouldallow it to perform a buffering function in addition to its role as achelator. It was only later that we learned that sodium valproate wascapable of buffering itself at much higher pH.

Sodium valproate is used clinically at concentrations of 100 mg/mL. Likeany weak acid, the valproate molecule will be charged above its pKavalue (4.8), and thus more readily soluble at high pH. Despite itscharged character at high pH, solubility limits in water are commonlyreported as 50-100 mg/mL. Indeed, this is quite concentrated for anysolute, with 100 mg/mL equivalent to a 10% solution. Given the reportedsolubility limit, we were surprised when our experiments demonstratedthat sodium valproate fully dissolves and forms clear, homogeneousaqueous solutions up to at least 500 mg/ml. Furthermore, given a pKa of4.8, it would be expected that a concentrated solution of sodiumvalproate would have a pH slightly above the pKa, perhaps even a wholepH unit above this value (≈5.5-6.0). However, a solution of 150 mg/mLsodium valproate in water yields a pH of approximately 8.3. Moreconcentrated solutions (>350 mg/mL) possess pH values above 9. Thisunexpected finding indicates that sodium valproate is much more solublethan is commonly reported.

In addition, the high pH of these solutions suggests that sodiumvalproate at high concentrations is capable of acting as a buffer wellabove its pKa. Typically, the useful range of a buffer is estimated tobe about 1 pH unit above/below its pKa. Thus, sodium valproate would beexpected to be useful as a buffer at pH 3.8-5.8. Accordingly, sodiumvalproate solutions should have little capacity to resist changes in pHoutside of this range. Indeed, we expected that solutions of sodiumvalproate could be easily titrated down to physiological pH (7-7.4), andthat this would require the addition of a buffer (e.g., phosphate, Tris,citrate) to maintain sodium valproate solutions in the physiological pHrange. Surprisingly, our experiments indicate that these concentratedsolutions of sodium valproate strongly buffer solutions at pH>8, andsignificant quantities of acid are required to lower the pH into thephysiological range. Again, considering the pKa of 4.8, one would expectminimal buffering of sodium valproate above pH 6, but this is not thecase. Accordingly, concentrated solutions of sodium valproate are notonly readily prepared by dissolving at room temperature, they bufferthemselves at pH values well above that predicted by their pKa. Thisunexpected property suggests that highly concentrated aqueous solutionsof sodium valproate are homogenous and maintain stable pH; suitable forparenteral administration and prolonged storage within a pump.

Concerns about potential precipitation during administration due toeither reduced pH or contaminating metal ions prompted us to exploresodium citrate as both a buffering component and a chelator of metalions. Because citrate has a pKa of 6.4, incorporation of citrate intosodium valproate solutions should fortify buffering in the physiologicalpH range, and also chelate trace metal ions that may becomesolubilized/released within the pump. Considering the unexpectedlystrong buffering by sodium valproate (described above), additionalbuffering capacity may not be necessary. Indeed, our results withsolutions of 150 mg/mL (0.9 M) sodium valproate with or without 0.4%sodium citrate (13.6 mM) indicate that this low level of citrate doesnot provide any measurable increase in buffering capacity above pH 7,nor does it significantly change the initial pH of these solutions.Nonetheless, inclusion of sodium citrate as a cation/metal chelatorprovide an improved formulation. It is worth noting that citrate isnaturally present in cerebral spinal fluid.

The preceding merely illustrates the principles of the invention. Itwill be appreciated that those skilled in the art will be able to devisevarious arrangements which, although not explicitly described or shownherein, embody the principles of the invention and are included withinits spirit and scope. Furthermore, all examples and conditional languagerecited herein are principally intended to aid the reader inunderstanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

That which is claimed is:
 1. A method of ameliorating a symptom ofepilepsy in a subject, comprising: administering directly to the brainof a subject a therapeutically effective amount of a medicament multipletimes over a time period of at least two days, thereby ameliorating thesymptom of epilepsy, determining medicament concentration by samplingcerebrospinal fluid from the lateral ventricle and performing a test ofmedicament concentration in the sampled cerebrospinal fluid, changingdaily flow rate and/or concentration of infused medication to achieve animprovement a clinical symptom, wherein the medicament comprisesvalproic acid or a pharmaceutically active derivative thereof; whereinthe concentration of the medicament is 100-500 mg/mL; wherein themedicament comprises a half-life of less than 2 hours in cerebrospinalfluid and wherein during treatment the medicament has a concentration inthe cerebrospinal fluid of between about 1 microgram/ml to 500micrograms/ml.
 2. The method of claim 1, wherein during treatment themedicament has a concentration in the cerebrospinal fluid of between 2microgram/mL, to 200 microgram/mL; and wherein the administeringdirectly to cerebrospinal fluid of the subject's brain, and issubstantially continuous administration of the medicament duringtreatment via a catheter.
 3. The method of claim 2, wherein theadministering directly to a subject's brain is via multiple bolus pulsesof the medicament during treatment.
 4. The method of claim 2, whereinadministering directly to a subject's brain is in multiple bolus pulsesof the medicament during treatment, and wherein a dosage is based upon atarget treatment dosage of the medicament and the medicament's half-lifein the cerebrospinal fluid such that the target treatment dosage duringa treatment period is multiplied by a number of half-lives lostoccurring during gaps in a treatment period to achieve meaningful targettherapeutic levels.
 5. The method of claim 2, wherein there is asubstantially linear relationship between a concentration of themedicament in the cerebrospinal fluid and a daily dosage of themedicament.
 6. The method of claim 2, further comprising: monitoringadministration of the medicament by monitoring the subject's perceptionof their own body temperature.
 7. The method of claim 2, wherein themedicament is administered as part of a pharmaceutical compositioncomprising citric acid.
 8. The method of claim 2, wherein the medicamentis only administered to one lateral brain ventricle on one side of thebrain and not bilaterally administered to both ventricles.
 9. A methodof ameliorating a symptom of epilepsy comprising: administering atherapeutically effective amount of a medicament with a catheterdirectly to the brain of a subject, wherein the medicament comprises ahalf-life of less than 2 hours in cerebrospinal fluid; determiningmedicament concentration by sampling cerebrospinal fluid from thelateral ventricle and performing a test of the concentration ofmedicament in the sampled cerebrospinal fluid; and changing daily flowrate and/or concentration of infused medication to achieve animprovement in a clinical symptom, wherein the medicament amelioratesand/or modifies the epilepsy, wherein the medicament comprises valproicacid or a pharmaceutically active derivative thereof, wherein theconcentration of the medicament is 100-500 mg/mL and wherein duringtreatment the medicament has a concentration in the cerebrospinal fluidof between about 1 microgram/ml to 500 micrograms/ml.
 10. The method ofclaim 9, wherein the medicament is in a formulation with a composition,comprising citric acid.
 11. The method of claim 10, wherein themedicament concentration is at least 150 mg/mL.
 12. The method of claim10, wherein the medicament concentration is at least 200 mg/mL.
 13. Themethod of claim 10, wherein the medicament concentration is at least 300mg/mL.
 14. A method of ameliorating seizures of a patient diagnosed withepilepsy, comprising: administering directly to cerebrospinal fluid of apatient's brain a formulation comprised of valproic acid or apharmaceutically acceptable salt thereof; continuing the administrationdirectly to cerebrospinal fluid of the patient's brain over a period ofdays; determining formulation concentration by sampling cerebrospinalfluid from the lateral ventricle and performing a test of theconcentration of the formulation in the sampled cerebrospinal fluid; andchanging daily flow rate and/or concentration of infused formulation toachieve an improvement in a clinical symptom, wherein the concentrationof the medicament is 100-500 mg/mL; wherein the medicament comprises ahalf-life of less than 2 hours in cerebrospinal fluid, wherein duringtreatment the medicament has a concentration in the cerebrospinal fluidof between about 1 microgram/ml to 500 micrograms/ml, and therebyameliorating seizures.